Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility

Haddon, Josephine E. ORCID: https://orcid.org/0000-0001-5975-813X, Titherage, Daniel, Heckenast, Julia R., Carter, Jennifer, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009, Wilkinson, Lawrence S. ORCID: https://orcid.org/0000-0002-9337-6124 and Jones, Matthew W. 2024. Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility. Translational Psychiatry 14 (1) , 256. 10.1038/s41398-024-02969-x

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Abstract

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1–BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/−) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/− rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/− rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Neuroscience and Mental Health Research Institute (NMHRI) Medicine Psychology MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	2158-3188
Funders:	Wellcome Trust, MRC
Date of First Compliant Deposit:	14 June 2024
Date of Acceptance:	29 May 2024
Last Modified:	01 Jul 2024 15:20
URI:	https://orca.cardiff.ac.uk/id/eprint/169835

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